Managing CKD Anemia with 2020 Vision Dan Martinusen Bsc(Pharm), ACPR, Pharmd, FCSHP Outline

Managing CKD Anemia with 2020 vision Dan Martinusen BSc(Pharm), ACPR, PharmD, FCSHP Outline

• Anemia – a few thoughts • How we got here – our Anemia Management Protocol • Recent evidence to consider – what the PIVOTAL trial adds to Normal Hematocrit, DRIVE, DRIVE 2, CREATE, CHOIR and TREAT • Comparing our protocol with PIVOTAL • HIF inhibitors and SGLT2 inhibitors • Steps moving forward for managing anemia in BC • Renal Community input • Incorporating PROMIS analytics Anemia A few thoughts Co-morbidities of CKD impacting outcomes • Anemia • Bone disease

• Cardiovascular disease(s) Multiple medications • Depression Multiple events Multiple interactions • Infections • Impaired cognition • Malnutrition

From Dr. A Levin Anemia : The Facts

• Hgb values vary within normal populations • Male vs female • “Bell curve” distribution • Altitude

• In all populations studied, lower Hgb is associated with poor outcomes • General populations • Disease specific • Cancer, CHF, GI, Autoimmune diseases • CKD, Dialysis and Transplant

From Dr. A Levin Chronic Kidney Disease Populations: Anemia • Important comorbidity • Multi-factorial : iron, ESA resistance, ESA deficiency (relative), inflammation

• Associated with symptoms : Patient reported outcomes… • Fatigue, cognitive dysfunction • Exercise intolerance

• Associate with adverse outcomes: • LVH, CHF and worsening angina symptoms • Transfusions: interfering with transplantability • CVE, hospitalizations • Death

From Dr. A Levin Consistent Association : All-Cause Mortality in CKD By GFR and anemia – 10-year ARIC Adjusted 10-year predicted probability of mortality (%) 40

20 Anemia

10 No anemia 0 30 45 60 75 90 105 120 135 150 Estimated GFR (mL/min/1.73m2)

Astor et al 2004 Anemia defined as Hb <13.5 g/dL in men, <12 g/dL in women From Dr. A Levin Association of Anemia in CKD : consistent and persistent Dialysis CKD • Ischemic Heart Disease x x • LVH x x • Impaired Quality of Life x x • Reduced Exercise Capacity x x • Impaired Cognition x • Hospital Stay x x • Mortality x x

From Dr. A Levin What has the “AMP” accomplished?

• Reduction in costs • Greater % of patients in target (Hemoglobin, TSAT, Ferritin) • Achieving target sooner • Avoiding harm (MI, hypertension, stroke, hospitalizations)? • Standardization based on evidence? • Fewer blood transfusions? • Lower death rate? • More vascular access thrombosis & infections?? BC Anemia Protocol CKD non-dialysis, dialysis, peritoneal dialysis

More iron reduces ESA dose safely

DRIVE DRIVE II Besarab et al (6 weeks)1 (6 weeks)2 (6 months)3

1 g IV iron IV iron weekly to maintain a HD >90 days Chronic HD TSAT of 30%–50% on ESA 25% ↑ in ESA dose ESA and iron On ESA R (held constant) per investigator R Ferritin 150–600 µg/L Ferritin 500–1200 µg/L TSAT 19%–30% IV iron weekly to maintain TSAT ≤25% No iron Hgb ≥95 g/L TSAT of 20%–30% Hgb ≤110 g/L N=42 N=134 • Among anemic patients with ‘high’ ferritin, IV • Increasing TSAT to 30%–50% among ‘iron- iron ↑ Hgb and allowed for ↓ ESA use replete’ patients allowed for ↓ ESA use • No safety signals emerged over 12 weeks • No differences in hospitalization or infection rates

DRIVE=Dialysis Patients’ Response to IV Iron w ith Elevated Ferritin. aIV iron administered initially as 4–6 doses of 100 mg to increase TSAT to >30% and thereafter as w eekly maintenance doses of 25–150 mg/wk to maintain TSAT of 30%–50%. 1. Coyne DW et al. J Am Soc Nephrol. 2007;18(3):975-984; 2. Kapoian T et al. J Am Soc Nephrol. 2008;19(2):372-379; 3. Besarab A et al. J Am Soc Nephrol. 2000;11(3):530-538. Overall results demonstrate IV iron spares ESA dose

O ptimal Iron Suboptimal Iron Mean Difference Mean Difference IV, Random, 95% CI [U × 1000] Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI DeVita, 2003 11,074 8,141 19 15,267 8,890 17 4,8% −4193.00 [−9783.93, 1397.93] Fishbane, 1995 8,100 5,670.7 20 15,126 4,276.6 32 12.3% −7026.00 [−9919.43, −4132.57 Fishbane, 2001 11,772 11,780 74 10,949 12,154 64 8.1% 823.00 [−3185.77, 4831.77] Kaneko, 2003 2,629 2,640 97 3,606 3,347 100 26.0% −977.00 [−1817.45, −136.55] Kotaki, 1997 9,400 4,405.5 15 10,062.5 5,420 16 9.9% −662.50 [−4129.99, 2804.99] Li, 2008 4,500 8,776.6 70 6,140 8,237.8 66 12.5% −1640.00 [−4499.53, 1219.53] Macdougall, 1996 5,259 1,002 12 6,041.4 1,367.5 25 26.4% -782.40 [−1562.63, −2.17]

Total (95% CI) 307 320 100.0% −1732.50 [−3072.78, −392.23]

−5 0 5 10 Favours (optimal iron) Favours (suboptimal iron) ‘Optimal iron’ allowed for a 23% ↓ in ESA dose (compared to “suboptimal iron”) The AMP is based on EVIDENCE • DRIVE & DRIVE 2 – ESA resistant anemia – give more & regular iron • Normal Hematocrit, CHOIR & CREATE – Hgb <130 g/L, ESA dose is key • TREAT – CKD not on dialysis use ESA sparingly, Hgb not above 120 (in fact, no advantage going above 115g/L 1998 2006 2006 2009 TREAT Normal Hematocrit Study CHOIR CREATE No CV or mortality benefit of hematocrit (42%) associated with ~30% ↑ 34% ↑ in death + MI + HF No benefit with normalizing + stroke with hemoglobin target of 4 darbepoetin alfa in patients with DM in the risk of death or nonfatal MI in HD 2 Hgb in ND-CKD 135 g/L in ND-CKD vs 113 g/L and ND-CKD; 92% ↑ in stroke5 (stopped prematurely)1 (2013): Independent of Hgb, higher (2011): Risk of stroke not related to Hgb6 ESA doses ↑ risk for CV events3

1. Besarab A et al. N Engl J Med. 1998;339(9):584-590; 2. Singh AK et al. N Engl J Med. 2006;355(20):2085-2098; 3. McCullough PA et al. Am J Nephrol. 2013;37(6):549-558; 4. Drüeke TB et al. N Engl J Med. 2006;355(20):2071- 2084; 5. PfefferMA et al. N Engl J Med. 2009;361(21):2019-2032; 6. Skali H et al. Circulation. 2011;124(25):2903-2908. By implementing our protocol, “these studies suggest” since 2009…* •We avoided: • 560 strokes • 162 cancer related deaths • 1813 events of death, MI, CHF hospitalization, stroke (a combined endpoint) • 1029 deaths • 1670 CHF hospitalizations *(but we don’t really know) • 1573 dialysis starts. (event # reduced by 50% to be conservative)

1. Besarab A et al. N Engl J Med. 1998;339(9):584-590; 2. Singh AK et al. N Engl J Med. 2006;355(20):2085-2098; 3. McCullough PA et al. Am J Nephrol. 2013;37(6):549-558; 4. Drüeke TB et al. N Engl J Med. 2006;355(20):2071- 2084; 5. PfefferMA et al. N Engl J Med. 2009;361(21):2019-2032; 6. Skali H et al. Circulation. 2011;124(25):2903-2908. INCREASED RELIANCE ON IV IRON INCREASED SERUM FERRITIN OVER TIME Trends in Serum Ferritin Concentrations in the US1,2 1000 KDIGO limit IV iron to TSAT <30% and ferritin <500 μg/L

g/L) Ferritin goal Ferritin goal

μ 800 200-800 200-500 Ferritin goal 100-800

600 ESA and IV iron bundled Mean Mean ( Ferritin in US

400

200 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018 Year KDIGO=Kidney Disease: Improving Global Outcomes; TSAT=transferrin saturation. Adapted from 1. Charytan DM et al. J Am Soc Nephrol. 2015;26(6):1238-1247; 2. US-DOPPS (Dialysis Outcomes and Practice Patterns Study) Practice Monitor. https://w ww.dopps.org/DPM/Files/meanferritinngml1_overallTAB.htm. Accessed September 10, 2018.

© Vifor Pharma 18 Changes in Practice British Columbia CKD patients Changes over time in EPO initiation practices: 2007- 2017 Median eGFR at EPO initiation 30 27 23 24 21 21 21 19 19 18 18 17 16 18 14 14 15 12 9 6 3 eGFR (mL/min/1.73m^2) eGFR 0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Year

Median Hemoglobin at EPO initiation 110 107 104 99 101 97 98 98 93.5 95 92 92 92 91 92 88 89 88 Hgb (g/L) 89 86 83 80 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Year n= 614 644 606 422 425 517 463 453 452 468 373

From Dr. A Levin …but questions remained about IV iron

High vs low ferritin threshold?

Iron vs ESA?

Ferritin vs TSAT?

Conservative vs liberal dosing strategies? Patients come in all shapes and sizes

38F ADPKD GFR 20

No CVD Symptoms Hb 105 Non- smoker

BP 115/75

From Dr. A Levin British Columbia CKD patients Changes over time in EPO initiation practices: 2007- 2017

% Hgb Level at EPO initiation overtime 60% 50% 40% 30% 20% 10% 0% 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 < 90 90-94 95-99 100-104 105-109 110-114 >=115

n= 614 644 606 422 425 517 463 453 452 468 373 From Dr. A Levin HIF inhibitors An oral agent coming soon for anemia… Anemia, CKD and HIF therapies

• Hypoxia-inducible factor (HIF) Prolyl Hydroxylase Inhibitors or HIF stabilizers • Oral medication • Stimulate iron absorption, endogenous EPO production • Inhibit proinflammatory cytokines • Act on multiple genes • ? Additional beneficial effects

From Dr. A Cunningham Mechanism of Action Conclusions Non-inferior to ESA in maintaining Hb level for stable patients who are relatively EPO responsive and iron replete Potential Concerns: Potential Benefits: - Higher rates of discontinuation - Oral medication - Adverse events, including hyperkalemia - Avoid ESAs - Iron mobilization in the absence of IV iron - Tumour progression - Suppression of inflammation - Pulmonary hypertension - Metabolism - Ischemic protection - Angiogenesis, DM retinopathy - Progression of CKD From Dr. A Cunningham - Thromboembolic events Current Therapies in Anemia in CKD • Various treatments work to raise Hb • Iron, ESA and HIF stabilizers

• Issues from clinical trial data: • Sick populations do not benefit from attempts to raise Hb with very high doses of ESA • Guidelines suggest narrow range of target Hb for non dialysis and dialysis pts • Adverse effects of ESAs in specific populations not well defined • Individualization of therapy

• Ongoing questions: • What level of Hb is appropriate for CKD, Dialysis pts? • What are appropriate outcome measures? • QOL, survival, exercise ability • Other From Dr. A Cunningham A diabetes drug for anemia?? Practical changes to AMP CKD non-dialysis, dialysis, peritoneal dialysis A need to know more…

“Studies should be conducted to “…aside from changes in laboratory determine whether treatment with parameters, the evidence base evaluatingiron has clinically relevant outcomes related to the use of IV iron is beneficial“There is effectsan urgent beyond need for RCTs sparse, and the effect of IV iron on hard stimulationto assess the of relativeerythropoiesis safety andin clinical outcomes including death and patientsefficacy withof IV CKDiron.” in the major health events is uncertain.” management of CKD-related anemia, particularly in relation to hard clinical end points, as well as infection risk and other patient- related outcomes.” Proactive IV irOn Therapy in hemodiALysis

• Largest study to date : 2141 HYPOTHESIS: patients • Trial was well conducted – we can Proactive, high-dose IV iron sucrose believe the results would be non-inferior to reactive, • Compared “proactive” to low-dose IV iron sucrose for the “reactive” iron sucrose dosing outcome of all-cause mortality and • Population similar to our HD CV events in HD patients. population

Macdougall IC et al. Am J Nephrol. 2018;48(4):260-268. PIVOTAL Design

Proactive, high-dose IV iron sucrose* arm (n=1093) IV iron sucrose 400 mg/month (withhold if ferritin >700 μg/L or TSAT ≥ 40%)

New to HD ≥631 primary (0–12 months) endpoint events n=2141 Iron held in both groups if active R (death, MI, On ESA infection present Ferritin <400 µg/L stroke, or HF TSAT <30% hospitalization) (N=2589) Reactive, low-dose IV iron sucrose* arm (n=1048) IV iron sucrose only administered if ferritin <200 μg/L or TSAT <20%

Adapted from Macdougall IC et al. Am J Nephrol. 2018;48(4):260-268. 1. Macdougall IC et al. Am J Nephrol. 2018;48(4):260-268; 2. Macdougall IC et al. [published online October 26, 2018; published correction appears in N Engl J Med. January 14, 2019. doi:10.1056/NEJMx180044]. N Engl J Med. doi:10.1056/NEJMoa1810742 PIVOTAL OUTCOMES

Primary Endpoint

Composite of nonfatal MI, nonfatal stroke, hospitalization for HF, or all-cause death, analyzed as time-to-first event

Components of the Primary Endpoint (Secondary Endpoints)

• All-cause death • Composite of CV events (MI, stroke, and hospitalization for HF [first event]) • MI (fatal or nonfatal) • Stroke (fatal or nonfatal) • Hospitalization for HF

Recurrent Events (Secondary Endpoint)

MI, stroke, hospitalization for HF, and deaths analyzed as first + recurrent events

Macdougall IC et al. Am J Nephrol. 2018;48(4):260-268. Additional Efficacy Endpoints

• ESA dose requirements • Quality-of-life measures • Transfusion requirements

Safety Endpoints

• Vascular access thrombosis • Hospitalization for infection • All-cause hospitalization • Infection episodes

Laboratory Endpoints

• Cumulative dose of iron • Platelet count • Hemoglobin concentration • Serum albumin concentratio n • Serum ferritin concentration • TSAT “Proactive” group had 119 mg more iron/month

11,000

10,000 Proactive, high-dose iron sucrose

9000 Patients in the proactive, BC Mean 8000 high-dose arm received a 7000 median of 2 g more IV BC Median iron sucrose by month 12 6000

5000

4000 Reactive, low-dose iron sucrose 3000 IV Iron Sucrose IV Iron Sucrose (mg)

2000 Mean (95% CI) Cumulative Mean (95% CI) Cumulative Median monthly doses: 1000 264 mg vs 145 mg P<0.001 at all timepoints 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time From Randomization (months)

Macdougall IC et al. [published online October 26, 2018; published correction appears in N Engl J Med. January 14, 2019. doi:10.1056/NEJMx180044]. N Engl J Med. doi:10.1056/NEJMoa1810742 Ferritin rose rapidly in higher dose iron group

750 700 650 g/L)

μ 600 ( 550 Proactive, high-dose iron sucrose 500 450 ) Ferritin ) Ferritin 400 350 300 Reactive, low-dose iron sucrose 250 200 Mean Mean (95% CI 150 100 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

. Macdougall IC et al. [published online October 26, 2018; published correction appears in N Engl J Med. January 14, 2019. doi:10.1056/NEJMx180044]. N Engl J Med. doi:10.1056/NEJMoa1810742 TSAT rose rapidly in higher dose iron group

26 Proactive, high-dose iron sucrose

22 Mean Mean (95% CI) TSAT (%) 20 Reactive, low-dose iron sucrose

18 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time From Randomization (months)

2100

1800 Dose

1500 ESA Reactive, low-dose iron sucrose

1200

900 (1000 IU) Cumulative

600 Median monthly doses 300 reduced by 19.4% Proactive, high-dose iron sucrose Mean (95%)Mean

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time From Randomization (months) Hgb rose rapidly in higher dose iron group

12.0

11.8

11.6 (g/dL)

11.4 Proactive, high-dose iron sucrose

11.2

11.0

10.8

10.6 Reactive, low-dose iron sucrose

10.4

Mean Mean (95% CI) Hemoglobin 10.2 Hemoglobin rises due to iron + ESA

10.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Time From Randomization (months) 1’ Endpoint: better outcome in higher dose iron group

60 3% ↓ in Death, MI, Stroke, or HF Hospitalization HR, 0.85 (95% CI, 0.73–1.00) 15% RRR Noninferiority P<0.001 Superiority P=0.04

40 32.3% vs 29.3%

20 Patients With Event (%) Event With Patients

0 0 0.5 1 1.5 2 2.5 3 3.5 Time (years) From the New England Journal of Medicine, Macdougall IC et al., Intravenous iron in patients undergoing maintenance hemodialysis, [published online October 26, 2018]. Macdougall IC et al. [published online October 26, 2018; published correction appears in N Engl J Med. January 14, 2019. doi:10.1056/NEJMx180044]. N Engl J Med. doi:10.1056/NEJMoa1810742 Less recurrent CV events in higher dose iron group

60 5.2% ARR in Recurrent Eventsa (23% RRR RR, 0.77 (95% CI, 0.66–0.92) Reactive, low-dose iron sucrose

Proactive, high-dose iron sucrose 20 No difference in death from any cause Primary Primary Endpoints per 100 Patients 0 0 1 2 3 Time (years)

aDeath from any cause, MI, stroke, and hospitalization for HF. Recurrent events plotted in the form of mean frequency functions using the method of Ghosh and Lin (Biometrics. 2000;56:554-562). From the New England Journal of Medicine, Macdougall IC et al., Intravenous iron in patients undergoing maintenance hemodialysis, [published online October 26, 2018].

20% RRR 2.4% ARR unadjusted or or HR, 0.80 (95% CI, 0.64–1.00) (16.0% vs 13.6%) MI Stroke Hospitalization for HF

31% RRR 2.6% ARR unadjusted MI HR, 0.69 (95% CI, 0.52–0.93) (9.7% vs 7.1%)

N/A HR, 0.90 (95% CI, 0.56–1.44) Stroke (3.1% vs 3.3%)

34% RRR 2.0% ARR unadjusted Hospitalization for HF HR, 0.66 (95% CI, 0.46–0.94) (6.7% vs 4.7%)

HR (95% CI) adjusted for stratification variables: vascular access, diabetic status, and time on dialysis. Macdougall IC et al. [published online October 26, 2018; published correction appears in N Engl J Med. January 14, 2019. doi:10.1056/NEJMx180044]. N Engl J Med. doi:10.1056/NEJMoa1810742 Higher dose iron group required less blood

40 3.5% ARR in transfusion HR, 0.79 (95% CI, 0.65–0.95) 21% RRR

Reactive, low-dose iron sucrose 21.6% vs

20 18.1%

Proactive, high-dose iron sucrose Patients With Event (%) Event With Patients 0 0 0.5 1 1.5 2 2.5 3 3.5 Time (years)

Proactive, Reactive, High-Dose Low-Dose IV Iron Sucrose IV Iron Sucrose (N=1093) (N=1048) Endpoint n (%) n (%) Hazard or Rate Ratio (95% CI) P Value

Vascular access thrombosis 262 (24.0) 218 (20.8) 1.15 (0.96–1.38) 0.12

All-cause hospitalization 651 (59.6) 616 (58.8) 1.01 (0.90–1.12) 0.90

Hospitalization for infection 323 (29.6) 307 (29.3) 0.99 (0.82–1.16) 0.92 63.3 69.4 Infection episodes 0.91 (0.79–1.05) N/A per 100 PY per 100 PY

0.8 0.9 1.0 1.1 1.2 1.3 1.4 Proactive, High-Dose Better Reactive, Low-Dose Better

BC (2018) PIVOTAL Canada (2017 per (iron gluc. N=1943, Iron suc N=243) (↑iron) DOPPS) Average TSAT (%) 27 26 24.5 ± 1.5%

Average Hemoglobin 105.0 112 105.8 ± 1.4 g/L (g/L) (% under 110 = 63 % over 130 = 2.5) Average Ferritin (μ/L) 686.5 ~625 372 ± 54

Median monthly Iron Iron Gluconate = 156 IQR 94-229 (191) 264 135 dose (mg) (Mean) Iron Sucrose = 100 IQR 50-192 (95)

Median weekly ESA Median: Epoetin 6000 (IQR 4000-12,000) 7,440 9913 ± 587 dose (units) Darbe 20 (IQR 10-40 mg) Mean: 8416 ± 400 (InCent HD) 7786 ± 400 (Comm HD)

Pivotal outcomes applied to BC 2009-2019 • BC =2464 hemodialysis patients in 2019 (3% growth per year) • Composite of nonfatal MI, nonfatal stroke, hospitalization for HF, or all-cause death = 3.0% ↓ = 763 fewer events • All-cause death = NSS • Composite of CV events (MI, stroke, and hospitalization for HF [first event]) = 2.4% ↓ = 611 fewer events • MI (fatal or nonfatal) = 2.6% ↓ = 662 fewer events • Stroke (fatal or nonfatal) = NSS • Hospitalization for HF = 2.0% ↓ = 509 fewer events • MI, stroke, hospitalization for HF, and deaths analyzed as first + recurrent events = 5.2% = 1323 fewer events • Blood transfusions = 3.5% ↓ = 891 fewer events So where does the BC AMP go from here??

• Our protocol is a “PROACTIVE” protocol (with a reactive “boost”) • Can we compress iron administration to the first week or two of the month? • Should we be less aggressive with iron? Change to 600 mg load? • Should we copy PIVOTAL in iron dosing? • Analyze regional differences • Personalize the protocol (ADPKD, EPO resistant vs. not)? • Change the protocol and monitor changes • Trial endpoints are more difficult to analyze Stay tuned and thank you!

Questions?